| First Author | Cosson MV | Year | 2019 |
| Journal | J Mol Cell Cardiol | Volume | 131 |
| Pages | 132-145 | PubMed ID | 31009605 |
| Mgi Jnum | J:275926 | Mgi Id | MGI:6305023 |
| Doi | 10.1016/j.yjmcc.2019.04.017 | Citation | Cosson MV, et al. (2019) Knockout of adenylyl cyclase isoform 5 or 6 differentially modifies the beta1-adrenoceptor-mediated inotropic response. J Mol Cell Cardiol 131:132-145 |
| abstractText | Although only beta2-adrenergic receptors (betaAR) dually couple with stimulatory G protein (Gs) and inhibitory G protein (Gi), inactivation of Gi enhances both beta1AR and beta2AR responsiveness. We hypothesize that Gi restrains spontaneous adenylyl cyclase (AC) activity independent of receptor activation. Subcellular localization of the AC5/6 subtypes varies contributing to the compartmentation of betaAR signaling. The primary objectives were to determine: (1) if beta1AR-mediated inotropic responses were dependent upon either AC5 or AC6; (2) if intrinsic Gi inhibition is AC subtype selective and (3) the role of phosphodiesterases (PDE) 3/4 to regulate beta1AR responsiveness. beta1AR-mediated increases in contractile force and cAMP accumulation in cardiomyocytes were measured from wild type, AC5 and AC6 knockout (KO) mice, with or without pertussis toxin (PTX) pretreatment to inactivate Gi and/or after selective inhibition of PDEs 3/4. Noradrenaline potency at beta1ARs was increased in AC6 KO. PDE4 inhibition increased noradrenaline potency in wild type and AC5 KO, but not AC6 KO. PTX increased noradrenaline potency only in wild type but increased the maximal beta1AR response in all mouse strains. PDE3 inhibition increased noradrenaline potency only in AC5 KO that was treated prior with PTX. beta1AR-evoked cAMP accumulation was increased more by PDE4 inhibition than PDE3 inhibition in wild type and AC5 KO that was amplified by Gi inhibition. These data indicate that beta1AR-mediated inotropic responses are not dependent upon either AC5 or AC6 alone. Inactivation of Gi enhanced beta1AR-mediated inotropic responses despite not coupling to Gi, consistent with Gi exerting a tonic receptor independent inhibition upon AC5/6. PDE4 seems the primary regulator of beta1AR signaling through AC6 in wild type. AC6 KO results in a reorganization of beta1AR compartmentation characterized by signaling through AC5 regulated by Gi, PDE3 and PDE4 that maintains normal contractile function. |
